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. Author manuscript; available in PMC: 2018 Mar 1.
Published in final edited form as: Nat Neurosci. 2017 May 22;20(7):917–926. doi: 10.1038/nn.4571

Figure 8. Blocking of PD-L1 or PD-1 signaling induces spontaneous pain and allodynia in a mouse melanoma model.

Figure 8

(a) Tumor growth after melanoma cell inoculation (MCI) in a hindpaw. Left, images of ipsilateral hindpaw (red arrow) and contralateral hindpaw and an isolated melanoma (top) at MCI-4w. Scales, 5 mm. Right, time course of tumor growth after MCI, revealed by hindpaw volume change. BL, baseline. *P<0.05, vs. BL, One-Way ANOVA, n = 25 mice/group. (b) Serum PD-L1 levels in sham control mice and melanoma-bearing mice (MCI-4w). *P<0.05, two-tailed Student’s t-test. n= 6 mice/group. (c,d) Time course of mechanical pain (c) and spontaneous pain (duration of licking/flinching, d) after MCI. Note that tumor growth is not associated with the development of mechanical allodynia and spontaneous pain. n = 21 and 25 mice/group. (e) Induction of spontaneous pain by soluble PD-1 (sPD-1) following i.pl. injection at MCI-4w. Note a rapid onset of spontaneous pain by sPD-1 within 30 min. *P<0.05, compared with vehicle, two-tailed Student’s t-test. n= 6 and 7 mic/group. (f) Induction of ongoing pain (CPP) in melanoma-bearing mice by sPD-1 (i.pl.). Left, paradigm for assessing CPP in a two-chamber test. Right, difference in time spent in drug-paired compartment between the pre-conditioning and post-conditioning phases. *P<0.05, two-tailed Student’s t-test, n= 7–8 mice/group. (g,h) Induction of mechanical allodynia (g, n=11 mice/group) and spontaneous pain (h, n=9 mice/group) by peri sciatic injection of PD-1-targeting siRNA (2 µg) but not by control non-targeting siRNA (NT, 2 µg), given at MCI-4w. *P<0.05, repeated measures Two-Way ANOVA (g) and two-tailed Student’s t-test (h). (i,j) Intravenous Nivolumab (3 and 10 mg/kg), given at MCI-4w (indicated with an arrow), induces mechanical allodynia (i, n=4–6 mice/group) and spontaneous pain 3 h after the injection (j, n=6 mice/group). *P < 0.05, compared with control human IgG4, repeated measures Two-Way ANOVA (i) and two-tailed Student’s t-test (j). (k,l) Intravenous Nivolumab (10 mg/kg, MCI-4w) increases spontaneous firing of afferent fibers in the sciatic nerve 3 h after the injection. (k) Traces of discharges in melanoma-bearing mice treated with Nivolumab and human IgG4 control. (l) Number of spikes in 2 hours after the treatment. *P<0.05, two-tailed student’s t-test, n = 5 mice/group. Data are expressed as mean ± s.e.m.